Vanilloid receptor-1 (VR, or TRPV1 (transient receptor potential vanilloid-1)), also known as capsaicin receptors, refer to the receptors on nerve membrane which are activated by the stimulating compounds such as capsaicin receptor (8-methyl-N-vanillyl-6-nonenamide) which is the pungent ingredient of pepper. The molecular biological cloning of these receptors was reported in 1997 (Caterina et al., Nature, 1997, 389, 816-824). The receptors are non-selective cation channel consisting of 6 transmembrane domains, are known for selective influx of calcium (Ca2+), and belong to TrP channel family.
TRPV1 is either activated or sensitized in response to simuli such as capsaicin, resiniferatoxin (RTX), heat (>43° C.), low pH, anandamide, lipid metabolites, etc., to play an important role as a molecular integrator in the bio-chemical noxious stimulus (Tominaga et al., Neuron, 1998, 21, 531-543; Hwang et al., PNAS, 2000, 97, 6155-6160). TRPV1 is highly expressed in the primary afferent sensory neuron, and reports say that this is also expressed in various other organs and tissues including bladder, kidney, lung, intestine, skin, central nervous system (CNS) and non-neuronal tissues (Mezey et al., PNAS, 2000, 97, 3655-3660; Stander et al., Exp. Dermatol. 2004, 13, 129-139; Cortright et al., BBRC, 2001, 281, 1183-1189). Further, TRPV1 proteins increase in diseases accompoanied with severe pains. Activation of TRPV1 in response to endogenous/exogenous stimuli induce neurogenic inflammation by not only transmitting noxious stimuli, but also isolating neuropeptides such as P(substance P), CGRP (Calcitonin Gene-Related Peptide). To be specific, while the TRPV1 knock-out mouse react normally to noxious physical stimuli, vanilloids decrease pain reaction and esthesia to thermal stimulus, and hyperalgesia to thermal stimulus almost does not appear even in inflammatory condition (Caterina et al., Science, 2000, 288, 306-313; Davis et al., Nature, 2000, 405, 183-187; Karai et al., J. Clin. Invest., 2004, 113, 1344-1352).
As explained above, the TRPV1 knockout mouse has reduced responsiveness to heat or noxious stimulus, suggesting increased possibility of using the TRPV1 antagonist for the purpose of preventing or treating a variety of pain conditions. The recent reports indicate that capsazepine, which is the known TRPV1 antagonist, reduces hyperalgesia induced by physical stimuli in inflammatory and neuropathic pain models (Walker et al., JPET, 2003, 304, 56-62; Garcia-Martinez et al., PNAS, 2002, 99, 2374-2379). Further, when the primary afferent sensory neuron is treated with the TRPV1 agonist such as capsaicin, neuronal function is further damaged, leading into neuronal cell death. However, the TRPV1 antagonist was reported to act against the neuronal function damage and cell death (Holzer P., Pharmacological Reviews, 43, 143-201; Mezey et al., PNAS, 2000, 97, 3655-3660).
TRPV1 is known to be expressed in the sensory neuron distributed over the entire area of the gastrointestinal tract, and particularly highly expressed in the inflammatory diseases including irritable bowel syndrome and inflammatory bowel disease (Chan et al., Lancet, 2003, 361, 385-391; Yiangou et al., Lancet, 2001, 357, 1338-1339). Further, it was reported that TRPV1 activation stimulates sensory neuron to thus induce secretion of neuropeptides which are well known for playing a decisive role of inducing gastrointestinal disorder such as gastro-esophageal reflux disease (GERD) and stomach duodenal ulcer (DU) (Holzer P., Eur. J. Pharmacol., 2004, 500, 231-241; Geppetti et al., Br. J. Pharmacol., 2004, 141, 1313-1320). Accordingly, TRPV1 antagonist is expected to be effective in the prevention and treatment of the above-mentioned gastrointestinal disorders.
The efferent nerve, which expresses TRPV1, is prevalently distributed on the mucous membrane of respiratory track. The bronchial hyper-responsiveness has a very similar mechanism as the hyperalgesia, and protons and lipoxygenase (LOX) products as the endogenous ligand for TRPV1 are well known as the main cause of asthma and chronic obstructive bronchitis (Hwang et al., Curr. Opin. Pharmacol., 2002, 235-242; Spina et al., Curr. Opin. Pharmacol. 2002, 264-272). Further, the asthma-causing substance such as particulate matters including air pollutants react specifically to TRPV1, and such reaction was reported as been suppressed by capsazepine (TRPV1 antagonist) (Veronesi et al., NeuroToxicology, 2001, 22, 795-810). Accordingly, the possibility of using TRPV1 antagonist to treat respiratory diseases was suggested. Overacted bladder and urinary incontinence are caused by a variety of central/peripheral nerve impairment or damages and TRPV1 expressed in the efferent nerves and urinary bladder epithelial cells play critical role in the bladder inflammation (Birder et al., PNAS, 2001, 98, 13396-13401). Further, the TRPV1 knockout mouse is anatomically normal, but exhibits non-voiding bladder contracts compared to the low contracts of a normal mouse, thereby suggesting possible influence of TRPV1 on the function of bladder (Birder et al., Nat. Neuroscience, 2002, 5, 856-860).
Recently, some TRPV1 agonists have been developed for treatment of bladder disorders. TRPV1 is distributed not only in the primary efferent sensory neurons, but also on human epidermal keratinocytes (Denda et al., Biochem. Biophys. Res. Commun., 2001, 291, 1250-1250; Inoue et al., Biochem Biophys Res Commun., 2002, 291, 124-129), involves in various noxious stimulus transmission and pains such as skin irritations and itching, and closed related with skin diseases and disorder due to neurogenic/non-neurogenic factors such as cause of skin inflammation. The above is supported by the report which suggested that capsazepin, i.e., TRPV1 antagonist, suppresses inflammatory mediators in human skin cells (Southall et al., J. Pharmacol. Exp. Ther., 2003, 304, 217-222).
For the past few years, many research results reported different roles of TRPV1. Among these, relationship between blood flow/pressure regulation and plasmid glucose concentration regulation or type 1 diabetes etiology was reported (Inoue et al., Cir. Res., 2006, 99, 119-31; Razavi et al., Cell, 2006, 127, 1123-1135; Gram et al., Eur. J. Neurosci., 2007, 25, 213-223). Further, report says that the TRPV1 knockout mouse shows less anxiety-related behavior than a litter of normal mouse (Marsch et al., J. Neurosci., 2007, 27(4), 832-839).
Meanwhile, use of the TRPV1 agonist as pain reliever was also reported (Korean Patent No. 556157). The pain relieving effect by the TRPV1 agonist has mechanism of action based on the desensitization of capsaicin-sensitive sensory neurons. That is, in the early treatment of TRPV1 agonist, temporary pain and stimulations are induced due to influx of cation by the activation of TRPV1, but then the desensitization is induced to block pain with respect to not only the agonist itself, but also the other noxious stimuli. Using such characteristic, analogs such as capsaicin (brand name: Zostrix), olvanil, nuvanil, or resiniferatoxin are in use or developing stage as the treatment for acute pains, chronic pains, neurological pains, neurological damage, rheumatoid arthritis, urinary incontinence, or skin diseases (Wriggleworth and Walpole, 1998, Drugs of the Future, 23, 531-538). However, TRPV1 agonist has drawbacks of initial stimulant actions including pains and stimulations.
Korean Patent No. 707123 discloses 4-(methylsulfonylamino)phenyl analog as TRPV1 antagonist having strong pain relieving effect and a pharmaceutical composition containing the same. Korean Patent Publication No. 2008-67361 discloses indazole analog as TRPV1 antagonist. Korean Patent Publication No. 2009-35701 discloses benzimidazole analog as TRPV1 antagonist and a preparation method thereof. Korean Patent Publication No. 2009-90386 discloses benzimidazole as TRPV1 antagonist, a pharmacological composition containing the same, and a treatment method using the same. Korean Patent Publication No. 2009-90347 discloses 0-substituted dibenzyl urea derivative as TRPV1 antagonist. US Patent Publication No. 2005-277631 discloses substituted monocyclic heteroaryl TRPV1 ligand and use thereof for various treatments.
Meanwhile, Korean Patent No. 556157 discloses leciniferatoxin analog of simple structure as TRPV1 agonist which provides strong pain relieving effect, and a pharmaceutical composition containing the same.
Further, International Patent Publication Nos. 06-101321 and 06-101318 disclose TRPV1 modulator having biphenyl partial structure, and Korean Patent Publication No. 2009-6098 discloses tetrahydropyrimidoazepin derivative as TRPV1 modulator. However, most conventional TRPV1 agonist and antagonists are produced by organic synthesis, and no report has been made so far regarding the naturally occurring substance which provides biological stability.
Meanwhile, pain relieving effect by TRPV1 activation and roles of TRPV1 regarding inflammation has been reported. Noxious stimuli such as lipopolysaccharide (LPS), tissue plasminogen activator (TPA) or inflammatory factor accelerate immune system to excessively induce inflammatory substances such as TNF-α, IL-6, prostaglandin and nitric oxide to thus induce inflammatory diseases. COX-2(cyclooxygenase-2) is an enzyme that synthesizes prostaglandin and is the main pro-inflammatory mediator. The recent researches provide interesting facts about the role of COX-2 in the TRPV1 activation. By way of example, researchers have found that apoptosis by TRPV1 activation was dependent on COX-2 (Eichele K et al., Pharm. Res., 2008). Studies have also found that TRPV1 agonist, i.e., glyceryl nonivamide suppress COX-2 expression b LPS and production of prostaglandin through NF-κB as transcription factor (Lin Y et al., J. Pharmacol. Exp. Ther., 2007), and that expression of COX-2 and production of prostaglandin by TPA is meaningfully suppressed by the TRPV1 agonist (i.e., capsaicin) (Chen C W et al., Br. J. Pharmacol, 2003). Further, as the studies focused on TRPV1 role in the inflammatory response have been reported, TRPV1 agonist is gaining increasing attention as inflammation treatment (Helyes Z et al., Am. J. Physiol. Lung. Cell. Mol. Physiol., 2007; Huang W et al., Hypertension, 2009). Given the fact that the intracellular TRPV1 signalling is directly related with arachidonic acid homeostasis and COX-2 metabolism, it will be possible to investigate the possibility of using COX-2 regulation by food-derived protein metabolite for a novel agonist of TRPV1 channel.
Accordingly, in an effort to find a naturally-occurring substance that can regulate TRPV1 activity, the present inventor was confirmed that the Maillard peptides separated from well-aged traditional soy sauce can act both as agonist and antagonist for TRPV1 and thus used as a modulator for modulating TRPV1 activity, and additionally, based on the ability to suppress COX-2 activity, can be efficaciously used as a pharmaceutical composition for preventing or treating inflammation-related diseases including pain, neurological diseases, urgent defecation, inflammatory bowel disease, respiratory diseases, urinary incontinence, overactive bladder, neurogenic/allergic/inflammatory skin diseases, skin, eye or mucosal irritation, hyperacusis, tinnitus, vestibular hypersensitivity, heart disease, etc. In addition, the Maillard peptide of the present invention can inhibit COX-2 activity, and therefore can be effectively used as a pharmaceutical composition for preventing or treating inflammation-related diseases or conditions such as rheumatic fever, influenza, cold, throat pain, headaches, toothaches, sprains, neuralgia, synovitis, rheumatoid arthritis, degenerative arthropathies, gout, ankylosing spondylitis, psoriasis, dermatitis, etc., and completed the present invention.